Coatings for drug delivery devices

ABSTRACT

A polymer coating for medical devices based on a polyolefin derivative. A variety of polymers are described to make coatings for medical devices, particularly, for drug delivery stents. The polymers include homo-, co-, and terpolymers having at least one olefin-derived unit and at least one unit derived from vinyl alcohol, allyl alcohol and derivatives thereof.

This is a divisional application of U.S. application Ser. No.10/011,346, filed on Nov. 12, 2001 now U.S. Pat. No. 7,585,516, theteaching of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a field of medical devices, especially thedevices used for delivery of drugs. More particularly, it is directed tocoatings for drug delivery devices, such as, for instance, drug elutingvascular stents.

2. Description of Related Art

In the field of medical technology, there is frequently a necessity toadminister drugs locally. To provide an efficacious concentration to thetreatment site, systemic administration of such medication oftenproduces adverse or toxic side effect for the patient. Local delivery isa preferred method in that smaller total levels of medication areadministered in comparison to systemic dosages, but are concentrated ata specific site. Thus, local delivery produces fewer side effects andachieves more effective results.

One commonly applied technique for local delivery of the drug is throughthe use of medicated stents. One method of medicating a stent is withthe use of a polymer coating impregnated with the drug.

References describe a variety of polymers which can be used to coatstents. Of particular interest is a copolymer of ethylene and vinylalcohol, also known as poly(ethylene-co-vinyl alcohol) or EVOH.Poly(ethylene-co-vinyl alcohol) is also known under the trade name EVALand is distributed commercially by Aldrich Chemical Company ofMilwaukee, Wis. EVAL is also manufactured by EVAL Company of America ofLisle, Ill.

EVAL is a product of hydrolysis of ethylene-vinyl acetate copolymers.Those having ordinary skill in the art of polymer chemistry willunderstand that EVAL may also be a terpolymer and may include up to 5%(molar) of units derived from styrene, propylene and other suitableunsaturated monomers. EVAL possesses a desirable impermeability tooxygen, bio- and blood-compatibility. EVAL is at least somewhathydrophobic and thus is somewhat insensitive to moisture.

While EVAL has been shown to be a very inert and biocompatible polymerwhich is quite suitable for use with medical vascular devices, some ofits properties can be improved. In particular, EVAL, due to a highconcentration of hydroxyl groups in the vinyl component-derived units ofthe macromolecule, has strong interchain hydrogen bonding, which makesthe polymer initially hard to dissolve in an organic solvent.

Accordingly, EVAL's solubility in organic solvents is limited. At thesame time, these hydroxyl groups are responsible for insufficient waterresistance, and in many applications EVAL does absorb more water thandesired.

EVAL also has a high degree of crystallinity, due to the presence of theunits of the macromolecule derived from the ethylene component, and alimited ability to fully control the release of drugs. EVAL's limitedability to fully control the release rate of some drugs below a certainmolecular size stems from an insufficient degree of hydrophobicity ofEVAL. This leads to a level of water absorption that causes the polymerto swell, increasing the polymer's porosity, and the diffusivity of thedrug.

An improvement over EVAL is desired, so that the polymer forming thestent coating has a higher degree of hydrophobicity and a lower degreeof crystallinity as compared to EVAL.

In view of the foregoing, it is very desirable to have alternativepolymeric materials suitable for the use with various medical devices,particularly, with stents for controlled drug delivery. These polymericmaterials should be bio- and blood-compatible, at least partiallyimpermeable to oxygen, melt-processable, have reduced crystallinity,high hydrophobicity, high tensile strength and flexibility, ability toprovide slower drug release rates, and be soluble in organic solvents.

The present invention provides a number of such polymers according tothe following description.

SUMMARY

The embodiments of this invention provide a number of polymers to beused in coatings with medical devices, particularly, with stents forcontrolled local delivery of drugs. The drugs to be delivered aregenerally incorporated into the coatings.

The polymers used in the embodiments of this invention can be dividedinto several categories. The first category includes copolymers of anolefin, typically, ethylene (but also propylene) with a vinyl componentcontaining a hydroxymethyl group. These vinyl components are derivativesof allyl alcohol. Examples of the polymers in this category includepoly(ethylene-co-allyl alcohol), a terpolymer poly(ethylene-co-allylalcohol-co-vinyl alcohol), poly(propylene-co-allyl alcohol),poly(ethylene-co-methallyl alcohol), a terpolymerpoly(propylene-co-allyl alcohol-co-vinyl alcohol), andpoly(propylene-co-methallyl alcohol).

The second category includes polymers having units derived from vinylalcohol, but no units derived from allyl alcohol. This group includespoly(propylene-co-vinyl alcohol), poly(ethylene-co-methvinyl alcohol),poly(propylene-co-methvinyl alcohol), and a terpolymerpoly(propylene-co-ethylene-co-vinyl alcohol).

Finally, the third category includes a homopolymer polyallyl alcohol.

In addition, the embodiments of this invention provide for a number ofcoatings fabricated from a variety of terpolymers. The terpolymers areobtained by co-polymerization of an olefin component with ahydroxyl-containing component. These terpolymers are discussed in detailbelow.

When a coating is made out of one of the polymers described above, adrug to be delivered in a localized fashion is incorporated into thecoating. Examples of the drugs include antiproliferative substances suchas actinomycin D, or derivatives and analogs thereof.

The active agent can also fall under the genus of antineoplastic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and/or antioxidantsubstances. Particular examples of these and other usable drugs andactive agents are provided below.

The drug is typically incorporated into a coating matrix on a drugdelivery stent, the coating made out of one of the polymers provided inthe embodiments of this invention. In addition, the coatings can be usedon the stent as a primer, rate release limiting membrane, and/orbiocompatible topcoat.

According to one aspect of this invention, a coating for medical devicesis provided, the coating comprising a polymer having a formula—[CH₂—CHR¹]_(m)[CH₂—CR²(CH₂OH)]_(n)—[CH₂—CH(OH)_(x)]_(o), wherein R¹ andR² is each selected, independently, from a group consisting of hydrogenand an alkyl group; m and n is each, independently, an integer within arange of between about 30 and about 7,600; o is an integer within arange of between 0 and about 7,600; and x equals 1 if o equals atleast 1. When R¹ or R² or both is an alkyl group, the alkyl group istypically, but not necessarily, a methyl group.

According to another aspect of this invention, a coating for medicaldevices is provided, the coating comprising a polymer having a formula—[CH₂—CH(CH₃)]_(p)—[CH₂—CR³ (OH)]_(q)—[CH₂—CH(CH₂OH)_(y)]_(r)—, whereinR³ is selected from a group consisting of hydrogen, and an alkyl group;p and q is each, independently, an integer within a range of betweenabout 30 and about 7,600; r is an integer within a range of between 0and about 7,600; and y equals 1 if r equals at least 1. As in theprevious aspect of this invention, when R³ is an alkyl group, the alkylgroup is typically, but not necessarily, a methyl group.

According to yet another aspect of this invention, a coating for medicaldevices is provided, the coating comprising a polymer selected from agroup consisting of poly(ethylene-co-α-methvinyl alcohol),poly(propylene-co-ethylene-co-vinyl alcohol), and polyallyl alcohol.

According to another aspect of this invention, a coating for medicaldevices is provided, the coating comprising a polymer, the polymer beinga terpolymer comprising one or more units derived from an olefin and oneor more units derived from an unsaturated hydroxylated monomer.

According to another aspect of this invention, a polymer coating formedical devices is provided, the coating comprising a polyolefinderivative.

According to yet another aspect of this invention, a polymericfilm-former for coatings for medical devices is provided, the polymercomprising a polyolefin.

DETAILED DESCRIPTION

A family of polymers used to make coatings for medical devices, inparticular, for drug delivery stent, is characterized by the presence ofa polyolefin backbone, pendant on which are alkyl, hydroxyl, and/orhydroxyalkyl groups.

It is known, that while EVAL has good oxygen-barrier properties and someresistance to water vapor, as well as good biocompatibility, itssolubility in organic solvents and its ability to provide slow drugrelease are limited. These drawbacks are caused by the strong hydrogenbonding between the hydroxyl groups, which makes the polymer initiallyhard to dissolve in a solvent, but which also leads to swelling of thepolymer in water.

All polymers disclosed below are somewhat related to EVAL, but havebetter properties for the purposes of making coatings for medicaldevices. Particularly, they possess a higher degree of hydrophobicityand lower degree of crystallinity as compared to EVAL.

The reason for such improved properties is that, compared with EVAL, thepolymers can be more hydrophobic, lowering the degree of water swelling.The polymers can also be more readily dissolved in organic solvents byhaving less hydrogen bonding, due to a lower hydroxyl content, and lesscrystallinity.

Improved hydrophobicity of these polymers lowers the equilibrium waterabsorption, allowing slower drug release than what is possible for ofEVAL.

For a polymer to be useful in a coating for a drug delivery device, itshould satisfy at least the following requirements. It should absorb notmore than about 5% of water (by weight). It should have an ultimatetensile strength of at least 3,500 psi (about 24.2 MPa), and, at thesame time, an ultimate elongation to failure exceeding 30%. It should besoluble in at least some organic solvents even if those as strong asdimethylsulfoxide (DMSO) are required. Generally, it should be possibleto make at least a 2% (by weight) solution of the polymer in a solvent,such as DMSO, DMAC, DMF, methanol, toluene, isopropyl alcohol,trifluoroethanol, hexafluoroisopropanol, and similar solvents.

All the polymers, copolymers and terpolymers according to theembodiments of this invention described below satisfy these criteria.

The following examples show the polymers, copolymers, and terpolymersused to make coatings for medical devices of the present invention.

Example 1 Poly(ethylene-co-allyl Alcohol)

This polymer has the formula: —[CH₂—CH₂]_(m)—[CH₂—CH(CH₂OH)]_(n)—.

The polymer is synthesized by free radical co-polymerization of ethyleneand methyl acrylate followed by treatment of the resultingpoly(ethylene-co-methyl acrylate) with a strong reducing agent, forinstance, a metal hydride. As a result of the reaction of reduction, thehydroxymethyl group of allyl alcohol is formed.

The polymer can also be synthesized by polymerization of ethylene withacrylic acid followed by reduction. Free radical polymerization of allylacetate with ethylene followed by base hydrolysis results in the samepolymer. This last reaction scheme has the advantage of not using costlymetal hydride reagents. The process of free radical polymerization,metal hydride reduction, and base hydrolysis mentioned above are knownto those having ordinary skill in the art.

The resulting polymer, poly(ethylene-co-allyl alcohol), is morehydrophobic and thus more soluble in organic solvents than EVAL and itcan be used to form coatings on medical devices.

Example 2 Poly(ethylene-co-allyl alcohol-co-vinyl Alcohol)

The polymer has the following formula:—[CH₂—CH₂]_(m)—[CH₂—CH(CH₂OH)]_(n)—[CH₂—CH(OH)]_(o)—. This terpolymercan be synthesized from several different sets of starting monomers.Ethylene, methyl acrylate and vinyl acetate can be copolymerized by freeradical initiators, followed by reduction with a strong reducing agent,such as a metal hydride, for instance, lithium aluminum hydride(LiAlH₄). Similarly, ethylene, allyl acetate, and vinyl acetate could bepolymerized and reduced to yield the same product.

Alternatively, ethylene, allyl acetate, and vinyl acetate could becopolymerized and the alcohol groups then formed by catalytic basehydrolysis of the acetate moieties. Lastly, the free radicalpolymerization product of ethylene, methylacrylate and vinyl acetate canfirst be base hydrolyzed to the corresponding alcohol and carboxylgroups. Hydride reduction of the carboxyl group completes the synthesisand requires less hydride reagent than that required in the firstreaction scheme.

Example 3 Poly(propylene-co-vinyl Alcohol)

The polymer has the formula —[CH₂—CH(CH₃)]_(m)—[CH₂—CH(OH)]_(n)—. Thispolymer is synthesized in a way similar to the synthesis of EVAL, exceptinstead of ethylene, propylene is copolymerized in the usual fashion, bya free radical process with vinyl acetate, followed by hydrolysis of theacetate groups of the resulting copolymer. The process is understood bythose having ordinary skill in the art. The final product is very likelyto be atactic, with a crystallinity adjustable by varying the monomerratios, and thus has a higher solubility in organic solvents than EVAL.

Example 4 Poly(propylene-co-allyl Alcohol)

The polymer has the formula —[CH₂—CH(CH₃)]_(m)—[CH₂—CH(CH₂OH)]_(n)—.This polymer is synthesized in a way similar to the synthesis ofpoly(ethylene-co-allyl alcohol) described in the Example 1, above, onlyhere a poly(propylene-co-methyl acrylate) precursor is used instead ofpoly(ethylene-co-methyl acrylate) precursor of the Example 1.

Example 5 Poly(propylene-co-allyl alcohol-co-vinyl Alcohol)

The polymer has the formula:—[CH₂—CH(CH₃)]_(m)—[CH₂—CH(OH)]_(n)—[CH₂—CH(CH₂OH)]_(o)—.

This terpolymer is synthesized in a manner similar to what is describedin Example 2, above. Of course, instead of ethylene, propylene is usedhere at the stage of copolymerization.

Example 6 Poly(ethylene-co-methallyl Alcohol)

The polymer has the formula —[CH₂—CH₂]_(m)—[CH₂—C(CH₃)(CH₂OH)]_(n). Theprecursor used to fabricate this polymer is the copolymer of ethyleneand methacrylic acid. The synthesis of this polymer is achieved byreduction of the carboxyl group of the precursor to the hydroxyl group.A second synthetic pathway would be co-polymerization of ethylene andmethyl methacrylate followed by reduction.

Example 7 Poly(propylene-co-methallyl Alcohol)

The polymer has the formula —[CH₂—CH(CH₃)]_(m)—[CH₂—C(CH₃)(CH₂OH)]_(n)—.It is synthesized in a manner similar to the synthesis ofpoly(ethylene-co-methallyl alcohol), described in Example 6, above,except instead of the poly(ethylene-co-methacrylic acid) precursor usedin Example 6, a poly(propylene-co-methacrylic acid) precursor is used.

Example 8 Poly(ethylene-co-methyinyl Alcohol)

The polymer has the formula —[CH₂—CH₂]_(m)—[CH₂—C(CH₃)(OH)]_(n)—. Thispolymer has a structure very similar to that of EVAL, the onlydifference being that the carbon in EVAL which bears the hydroxyl groupis also substituted with a methyl group. Consequently, the properties ofthis copolymer are similar to those of EVAL. However, it can bebeneficially distinguished from EVAL in that its solubility in organicsolvents, due to the presence of an extra methyl group, is better thatthe solubility of EVAL.

This copolymer can be synthesized by saponification of the acetategroups of a poly(ethylene-co-methyinyl acetate) (also known aspoly(ethylene-co-isopropenyl acetate)) precursor. The preparation ofthis precursor as well as the saponification are conducted in a commonmanner known to those skilled in the art.

Example 9 Poly(propylene-co-methyinyl Alcohol)

The polymer has the formula —[CH₂—CH(CH₃)]_(m)—[CH₂—C(CH₃)(OH)]_(n)—.This polymer is anticipated to have an amorphous structure due to thepresence of atactic propylene groups. Its synthesis is analogous to thatof poly(ethylene-co-methyinyl alcohol) described in Example 8, above.The synthesis here involves the saponification of the acetate groups ofa poly(propylene-co-methvinyl acetate) precursor according to usualmethods known to persons having ordinary skill in the art of polymerchemistry.

Example 10 Poly(propylene-co-ethylene-co-vinyl Alcohol)

The polymer has the formula:—[CH₂—CH(CH₃)]_(m)—[CH₂—CH₂]_(n)—[CH₂—CH(OH)]_(o)—. This terpolymer madeby substituting some of the ethylene in the current synthesis of EVALwith propylene. This leads to lower crystallinity and increasedhydrophobicity of this polymer as compared to EVAL, while retaining allbeneficial properties of EVAL.

Example 11 Polyallyl Alcohol

This homopolymer has the formula —[CH₂—CH(CH₂OH)]_(m)—. It can besynthesized in any common way known to those having ordinary skill inthe art, including free radical polymerization of allyl alcohol.However, polyallyl alcohol is not easily synthesized from allyl alcoholto high molecular weight by conventional free radical polymerizationtechniques due to degradative chain transfer reactions.

One technique disclosed in the U.S. Pat. No. 3,285,897 to Sullivan, et.al. utilizes polymerization at high pressure in the presence of a freeradical polymerization catalyst. U.S. Pat. No. 6,096,393 to Ikeda, et.al. discloses several synthetic pathways including free radicalpolymerization of methacrylic acid or methyl methacrylate followed byreduction with a metal hydride.

Polyallyl alcohol is hydrophobic and not soluble in water, but issoluble in some rather strong organic solvents, such as dioxane,tetrahydrofuran, or methanol. Its oxygen barrier properties areexcellent.

In general, for any polymer, copolymer, or terpolymer discussed inExamples 1-11 above, as the content of the olefinic moiety in thepolymer, copolymer, or terpolymer increases, its elongation to failurealso increases, while both its capacity to absorb water and its ultimatetensile strength decrease.

In order to achieve the desired water absorption as well as desiredmechanical properties (ultimate tensile strength, elongation to failure)and solubility, the ratio of monomers is adjusted to yield a polymerhaving the properties in the desired range. Accordingly, the ratios forthe monomers used to obtain polymers, copolymers, and terploymers ofExamples 1-11 should be within a range as shown in Table 1.

TABLE 1 Compositions of (Co)polymers of Examples 1-11. Example No.Monomer 1 Monomer 2 Monomer 3 Total 1 Ethylene Allyl Alcohol None m + n== m = 30-7,600 n = 30-7,600 300-8,400 2 Ethylene Allyl Alcohol VinylAlcohol m + n + o == m = 30-7,600 n = 30-7,600 o = 30-7,600 600-4,200 3Propylene Vinyl Alcohol None m + n == m = 30-7,600 n = 30-7,600300-8,400 4 Propylene Allyl Alcohol None m + n == m = 30-7,600 n =30-7,600 300-8,400 5 Propylene Allyl Alcohol Vinyl Alcohol m + n + o ==m = 30-7,600 n = 30-7,600 o = 30-7,600 300-8,400 6 Ethylene MethallylAlcohol None m + n == m = 30-7,600 n = 30-7,600 300-8,400 7 PropyleneMethallyl Alcohol None m + n == m = 30-7,600 n = 30-7,600 300-8,400 8Ethylene Methvinyl Alcohol None m + n == m = 30-7,600 n = 30-7,600300-8,400 9 Propylene Methvinyl Alcohol None m + n == m = 30-7,600 n =30-7,600 300-8,400 10 Propylene Ethylene Vinyl Alcohol m + n + o == m =30-7,600 n = 30-7,600 o = 60-3,800 300-8,400 11 Allyl alcohol None Nonen = 30-7,600

In addition to the above-discussed eleven examples describingembodiments of this invention, there exist a large number of polymersthat can be also used to make coatings for medical instruments,particularly, for controlled drug delivery stents.

Such polymers comprise products of copolymerization of an olefinco-monomer component and a hydroxylated monounsaturated co-monomercomponent. Typically, one of the olefin components is mixed andco-polymerized with any two of the hydroxylated components, or viceversa, one of the hydroxylated components is mixed and co-polymerizedwith any two of the olefin components.

The process of co-polymerization usually involves a free radicalco-polymerization, but any other otherwise acceptable method ofco-polymerization known to those skilled in the art can be used as well.A large number of terpolymers is, thus, available as a result.

Examples of an olefin component comprise ethylene, propylene, and anybutene. Generally, any olefin, straight-chained or branched, havingbetween two and eight carbons can be used. Using olefins with largernumber of carbon atoms is not advisable because polymerization will bedifficult since the reactivity of such olefins will be decreased due totheir increased bulkiness and an increase in steric hindrance.

Examples of a hydroxylated monounsaturated component include vinylalcohol and its derivatives (i.e., methvinyl alcohol and the like),allyl alcohol and its derivatives (i.e., methallyl alcohol and thelike), 1-hydroxy-2-methyl ethylene, 1-hydroxy-2-methyl propene, and anumber of butene-ols (i.e., 3-butene-1-ol, 3-butene-2-ol, 3-butene-3-ol,3-butene-4-ol and 2-butene-1-ol).

Obviously, by matching various combinations of olefinic components withhydroxylated monounsaturated components, a very large number ofterpolymers may be obtained. The longer and the bulkier the groups onthe polymer backbone, the less is the polymer's tendency to crystallize.This is a positive feature of such bulkier macromolecules, because theirability to dissolve in organic solvents is increased.

It should be also borne in mind, than every time a vinyl alcohol groupis present, it was either created by saponification or reduction of anacetate moiety. Therefore, the polymers having the acetate group onlypartially converted to hydroxyl functionality are also included in thelist of the embodiments discussed above. Obviously, such polymers willhave both acetate and vinyl alcohol groups. In addition to the productshaving vinyl alcohol groups, some other above-mentioned terpolymers arealso obtained by saponification of the acetate moieties. Suchterpolymers include those based on 3-butene-3-ol, 3-butene-4-ol, and1-hydroxy-2-methyl-propene.

A polymer of this invention is used on a medical device, particularly,on a drug delivery stent. The invention is used as a coating matrix onthe stent. The coating polymer can have several functions. The coatingcan be used as a primer, as a matrix carrying the drug, as a raterelease limiting membrane and/or as a bio- and/or blood-compatibletopcoat.

In any of these cases, the coating is applied onto the stent by acommonly used method known to the practitioners of the art, forinstance, by spraying, dipping or molding, as described in Examples 12and 13, below. The drug can be incorporated within the coating, or thedrug can be in a separate layer underneath the coating, or the drug canbe adsorbed onto the surface of the coating.

Example 12 Poly(ethylene-co-allyl alcohol) Based Coating

Poly(ethylene-co-allyl alcohol), the polymer of Example 1 above, issynthesized with a monomer ratio (by moles) of about 1:1. The molecularweight of ethylene is 28 and of allyl alcohol—58, and both “m” and “n”are equal to a value of about 870. A number average molecular weight ofthe polymer is about 75,000. The polymer is dissolved in a mixture ofsolvents comprising 50% of DMSO and 50% of DMAC (by weight) to form a 2%solution (by weight).

A spray apparatus, such as an EFD 780S spray nozzle with a VALVEMATE7040 control system, manufactured by EFD, Inc. of East Providence, R.I.is used to apply the polymer solution to a stent. The EFD 780S spraynozzle is an air-assisted external mixing atomizer. The composition isatomized by air and applied to the stent surfaces. During the process ofapplying the composition, the stent can be optionally rotated about itslongitudinal axis, at a speed of 50 to about 150 rpm. The stent can alsobe linearly moved along the same axis during the application.

The 2% solution of the polymer is applied to a 13-mm TETRA stent(available from Guidant Corporation) in a series of 10-second passes, todeposit 10 μg of coating per spray pass. Between the spray passes, thestent is dried for 10 seconds using flowing air with a temperature of60° C. Five spray passes are applied to form a 50 μg primer layer,followed by baking the primer layer at 140° C. for one hour.

A drug containing formulation is prepared comprising 2% of the polymer,0.66% of actinomycin D and 97.34% of a mixture of solvents comprising50% of DMSO and 50% of DMAC. All percentage amounts are by weight. In amanner identical to the application of the primer layer, five spraypasses are performed to form a 50 μg drug-polymer layer, followed bybaking the drug-polymer layer at 50° C. for 2 hours.

Finally, a topcoat composition to control the drug release rate isprepared, comprising 2% of the polymer and 98% of a mixture of solventscomprising 50% of DMAC, 20% of DMSO and 30% of ethanol. All percentageamounts are by weight. In a manner identical to the application of theprimer layer and the drug-polymer layer, thirty-five spray passes areperformed to form a 350 μg topcoat layer, followed by final baking at50° C. for 2 hours.

Example 13 Poly(propylene-co-vinyl alcohol) Based Coating

Poly(propylene-co-vinyl alcohol), the polymer of Example 3 above, issynthesized with a monomer ratio of the propylene segments and the vinylalcohol segments (by moles) of about 44:56. The molecular weight ofpropylene is 42 and of vinyl alcohol 44. The value for “m” in thepolymer is about 765, and for “n”—about 974. A number average molecularweight of the polymer is about 75,000. The free radical polymerizationresults in the propylene component being atactic. The polymer isdissolved in DMAC to form a 2% solution (by weight).

Using the process and equipment described in Example 12, above, the 2%solution of the polymer is applied to a 13-mm TETRA stent. Five spraypasses are applied to form a 50 μg primer layer, followed by baking theprimer layer at 140° C. for one hour.

A drug containing formulation is prepared comprising 2% of the polymer,1% of β-estradiol and 97% of DMAC. All percentage amounts are by weight.In a manner identical to the application of the primer layer, thirtyspray passes are performed to form a 300 μg drug-polymer layer, followedby baking the drug-polymer layer at 50° C. for 2 hours.

Finally, a topcoat composition to control the drug release rate isprepared, comprising 2% of the polymer and 98% of a mixture of solventscomprising 70% of DMAC and 30% of ethanol. All percentage amounts are byweight. In a manner identical to the application of the primer layer andthe drug-polymer layer, thirty spray passes are performed to form a 300μg topcoat layer, followed by final baking at 50° C. for 2 hours.

The stent, or other implantable medical device can be used in any partof the vascular system, including neurological, carotid, coronary,renal, aortic, iliac, femoral or any other peripheral vascular lumens.The are no limitations on the size of the implantable medical device,its length, diameter, strut thickness or pattern. Examples of suchimplantable devices include self-expandable stents, balloon-expandablestents, stent-grafts, grafts (e.g., aortic grafts), artificial heartvalves, cerebrospinal fluid shunts, coronary shunts, pacemakerelectrodes, and endocardial leads (e.g., FINELINE and ENDOTAK, availablefrom Guidant Corporation). The underlying structure of the device can beof virtually any design. The device can be made of a metallic materialor an alloy such as, but not limited to, cobalt chromium alloy(ELGILOY), stainless steel (316L), “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devicesmade from bioabsorbable or biostable polymers could also be used withthe embodiments of the present invention.

There no limitations on the drugs to be incorporated within the coating.For example, the active agent of the drug could be designed to inhibitthe activity of vascular smooth muscle cells. It can be directed atinhibiting abnormal or inappropriate migration and/or proliferation ofsmooth muscle cells to inhibit restenosis.

Generally speaking, the drug can include any substance capable ofexerting a therapeutic or prophylactic effect in the practice of thepresent invention. The drug may include small molecule drugs, peptides,proteins, oligonucleotides, or double-stranded DNA.

Examples of the drugs which are usable include antiproliferativesubstances such as actinomycin D, or derivatives and analogs thereof.Synonyms of actinomycin D include dactinomycin, actinomycin IV,actinomycin I₁, actinomycin X₁, and actinomycin C₁.

The active agent can also fall under the genus of antineoplastic,anti-inflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antimitotic, antibiotic, antiallergic and antioxidantsubstances. Examples of such antineoplastics and/or antimitotics includepaclitaxel, docetaxel, methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride, and mitomycin.

Examples of such antiplatelets, anticoagulants, antifibrin, andantithrombins include sodium heparin, low molecular weight heparins,heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin andprostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone(synthetic antithrombin), dipyridamole, glycoprotein IIb/IIIa plateletmembrane receptor antagonist antibody, recombinant hirudin, andthrombin.

Examples of such cytostatic or antiproliferative agents includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril,cilazapril or lisinopril, calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil(ω-3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suramin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide.

An example of an antiallergic agent is permirolast potassium. Othertherapeutic substances or agents which may be appropriate includealpha-interferon, genetically engineered epithelial cells, rapamycin anddexamethasone.

Having described the invention in connection with several embodimentsthereof, modification will now suggest itself to those skilled in theart. As such, the invention is not to be limited to the describedembodiments.

1. A coating for a medical device, the coating comprising a polymerhaving a formula:

wherein R¹ is selected from a group consisting of a hydrogen atom and analkyl group; and R² is selected from a group consisting of a hydrogenatom and an alkyl group, wherein the coating contains a drug, and m isan integer within a range of between about 30 and about 7,600; n is aninteger within a range of between about 30 and about 7,600; o is aninteger within a range of between 0 and about 7,600; and x equals 1 if oequals at least
 1. 2. The coating of claim 1, wherein the alkyl group ismethyl.
 3. The coating of claim 1, wherein the polymer absorbs not morethan 5% of water by mass.
 4. The coating of claim 1, wherein the polymeris soluble in an organic solvent.
 5. The coating of claim 1, wherein thepolymer has a tensile strength of not less than about 24 MPa (3,500pounds per square inch).
 6. The coating of claim 1, wherein the polymerhas an ultimate elongation exceeding 30 percent.
 7. A coating for astent, the coating comprising a polymer having a formula:

wherein R¹ is selected from a group consisting of a hydrogen atom and analkyl group; and R² is selected from a group consisting of a hydrogenatom and an alkyl group; m is an integer within a range of between about30 and about 7,600; n is an integer within a range of between about 30and about 7,600; o is an integer within a range of between 0 and about7,600; and x equals 1 if o equals at least
 1. 8. The coating of claim 7,wherein the coating is a primer layer.
 9. The coating of claim 7,wherein the coating is a rate release limiting membrane.
 10. The coatingof claim 7, wherein the alkyl group is methyl.
 11. The coating of claim7, wherein the polymer absorbs not more than 5% of water by mass. 12.The coating claim 7, wherein the polymer is soluble in an organicsolvent.
 13. The coating of claim 7, wherein the polymer has a tensilestrength of not less than about 24 MPa (3,500 pounds per square inch).14. The coating of claim 7, wherein the polymer has an ultimateelongation exceeding 30 percent.